Familial Pancreatic Cancer (FPC) accounts for an estimated 5-10% of all pancreatic cancer and is one area of hope in this otherwise highly lethal malignancy. In this proposal, we plan to identify the mutant gene that was inherited in patients using a series of new pancreatic cancer cell lines from patients in families with multiple pancreatic cancers. We will use the same approach and team that recently identified another gene (Palb2) that causes the disease. Once we find additional genes in Specific Aim 1, we will determine their prevalence in 96 additional affected families in Specific Aim 2. The work has important implications for: early detection, genetic counseling and possibly treatment, as follows: Once the gene is known, we will be able to identify which family members need aggressive surveillance for early detection and which have only population risk. Additionally, we will be able to counsel families about their risk of transmitting the disease to their offspring. Finally, one known cause of familial pancreatic cancer is germline BRCA2 gene defects and these cancers are uniquely sensitive to parp inhibitors. It is possible that any new defect will cause similar defects in double strand break repair or will be synthetic lethal with an existing chemotherapeutic drug. Hypothesis: FPC germline predisposition mutations explain the majority of FPC. Specific Aim 1: Perform whole-genome sequencing of 9 novel FPC cell lines and germline DNA. Analyze and assemble a list of candidate familial predisposition genes. Specific Aim 2: Confirm and determine the initial prevalence of the predisposition gene in germline samples from 96 additional patients with FPC. PUBLIC HEALTH RELEVANCE: In 2010, more than 95% of pancreatic cancer patients will die of the disease within 5 years. One shining light is the potential to target patient's cancers that arose in a family cancer setting because they bear two defective copies of a DNA repair gene, an Achilles' heel. In this proposal we plan to discover all genes that cause familial pancreatic cancer and determine their prevalence.